The invention relates to a transdermal therapeutic system for the administration of active substances to the skin with a backing layer remote from the skin, an active substance depot, an active substance delivery control device controlling the delivery of the active substance through the system and a contact adhesive fixing means for the therapeutic system to the skin, and to the use thereof.
Such transdermal systems with several active substances depots are e.g. known from P 36 29 404.0, in which one or more isolated active substance depots, which are not interconnected, are arranged in an active substance distribution matrix.
This known arrangement is particularly preferred for solid or very viscous materials, the highly concentrated active substance permeating into the active substance distribution matrix and from there flows onto the optionally contact adhesive control membrane.
In the case of flowable active substances or active substance formulations, the active substance is frequently received in bag-like recesses of a matrix or in a bag formed by a controlling membrane or a film. When the active substance reservoir is exhausted, there is a rapid decrease in the internal pressure and of the migration speed of the active substance, too. Another disadvantage of systems with large bag-like units with a fluid active substance formulation is that they are sensitive to pressure and on the system being loaded by pressure, the complete active substance passes uncontrollably out of a burst bag into the active substance distribution matrix and the delivery of the active substance to skin then no longer takes place in controlled form. This is particularly undesired if it is a highly effective active substance, whose overdosing leads to risks.
Another disadvantage of the known systems is that they cannot be subdivided, e.g. for children and adults requiring less active substance different sizes have to be kept in stock
Finally, in the case of a plaster with a larger liquid reservoir, as a result of gravity action a non-uniform distribution of the liquid occurs, which significantly impairs the uniformity of active substance delivery.
The problem of the present invention is therefore to avoid the aforementioned disadvantages of the prior art and to provide a novel transdermal therapeutic system, which permits more reliable handling, particularly of liquid active substances or active substance formulations.
According to the invention this problem is solved by a transdermal therapeutic system, which is characterized in that the active substance depot is a multichamber system, in which discrete chambers have one or more active substances.
A multichamber system is advantageous, because the distribution of the active substance is better and possibly the cutting off or separating of part of the transdermal therapeutic system does not lead to the flowing or dropping out of the complete active substance formulation. Furthermore, flowable active substance formulations can only move to a limited extent under the action of gravity or pressure, so that even under the influence of gravity a relatively uniform distribution of an active substance-containing liquid can be obtained. If as a result of pressure loading an active substance chamber bursts, the remaining chambers remain undamaged, so that the function of the system is to a certain extent maintained, which is a precautionary measure reducing overdosing risks in the case of highly effective liquid active substances.
An advantageous further development of the inventive concept consists of the individual chambers being at least partly interconnected by channels in such a way that a flow of the chamber content for pressure compensation purposes is possible.
It can be advantageous for the connecting channels between the chambers to have an internal diameter such that they permit the through flow of the active substance fluid only when pressure is applied. This embodiment avoids the bursting of the depot and therefore to the system being made unusable under pressure loading, e.g. on application to animals in veterinary medicine such a pressure distributing means is useful.
It is also possible for the multichamber system to be purely a channel system.
The chambers can in each case have optionally different active substance delivery control means. This embodiment is particularly appropriate if different active substances are used in a system, in which said active substances are to be supplied to the skin with different delivery rates.
The chambers can be arranged in one or more identical or different active substance distribution matrices, which can be superimposed and/or juxtaposed.
An inventive transdermal therapeutic system preferably has an interrupted or uninterrupted contact adhesive layer as the fixing means to the skin.
The transdermal therapeutic system can also have one or more contact adhesive layers between the backing layer and the fixing device. This is particularly necessary and appropriate if the active substance distribution matrix is not contact adhesive and the non-permeable backing layer can only be applied via a further contact adhesive layer.
The inventive system is particularly advantageously used with a liquid active substance or substances, or in solution.
In multichamber systems, desired breaking lines can be provided between individual chambers and optionally in the backing layer and other layers. Such desired breaking lines permit a division of the system if a smaller active substance delivery is desired. This can e.g. avoid expensive storage of transdermal systems of different sizes and doses.
The chambers can be arranged at different height levels of the plaster, optionally in different distribution matrixes. The multichamber system can be arranged in a contact adhesive active substance distribution and control matrix.
The multichamber system can comprise active substance or active substance solution-filled films with control action, which are permeable for the active substance, optionally also in controlling manner and which are welded together to form a multichamber system.
The inventive therapeutic system can be used for the packing and administration of transcutaneously applicable active substances for human and veterinary medicine, as well as in cosmetics.
The depot can also have inert adjuvants. The term "inert" is here understood to mean that active substance and adjuvant do not react with one another. An "inert" adjuvant can also be a substance having physiological effects, such as e.g. DMSO or the like, which e.g. increases the permeability of the skin. The adjuvants can also be constituted by support materials, which make the active substance depot insensitive with respect to pressure and tension application, as well as carriers.
It is possible to use active substances which can be applied in transdermal manner and typical examples of these ar given below.
Nicotine
Corticosteroids:
hydrocortisone, prednisolone, beclomethasone-proprionate, flumethasone, triamcinolone, triamcinolone-acetonide, fluocinolon, fluocinolin-acetonide, fluocinolon-acetonide-acetate, clobetason-proprionate, etc.
Analgesics, anti-inflammatory agents:
acetaminophen, mefenamic acid, flufenamic acid, diclofenac, diclofenac-sodium-alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicyclic acid, 1-menthol, camphor, sulindac-tolmetin-sodium, naproxen, fenbufen, etc.
Hypnotically active sedatives:
phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, haloperidol, etc.
Tranquilizers:
fluphenazine, thioridazine, lorazepam, flunitrazepam, chloropromazine, etc.
Antihypertensives:
pindolol, bufralol, indenolol, nifedipine, lofexidin, nipradinol, bucumolol, etc.
Antihypertensively acting diuretics:
hydrothiazide, bendroflumethiazide, cyclobenthiazide, etc.
Antibiotics:
penicillin, tetracycline, oxytetraccline, fradiomycinsulphate, erythromycin, chloramphenicol, etc.
Anesthetics:
lidocaine, benzocaine, ethylaminobenzoate, etc.
Antimicrobiological agents:
benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc.
Antifungal agents:
pentamycin, amphotericin B, pyrrolnitrin, clotrimazole, etc.
Vitamins:
vitamin A, ergocalciferol, chlolecalciferol, octotiamine, riboflavin butyrate, etc.
Antiepileptics:
nitrazepam, meprobamate, clonazepam, etc.
Coronary vasodilators:
nytroglycerol, dipyridamole, erythritol tetranitrate, pentaerythritol tetranitrate, propatylnitrate, etc.
Antihistamines:
diphenyl hydromine hydrochloride, chlorpheniramine, diphenylimidazole, etc.
Antitussives:
dertromethorphan (hydrobromide), terbutaline (sulphate), ephedrine (hydrochloride), salbutanol (sulphate), isoproterenol (sulphate, hydrochloride), etc.
Sexual hormones:
progesterone, etc.
Thymoleptics:
doxepin, etc.
Further medicaments/pharmaceuticals:
5-fluorouracil, fentanyl, desmopressin, domperdon, scopolamine (hydrobromide), peptide, etc.
Obviously this list is not exhaustive.
Advantageously the active substance matrix can be built up in layer form, the layers being the same or different. The active substance matrix can be contact adhesive and can e.g. be a rubber material, such as styrene/isoprene/styrene block copolymers, silicone rubber or synthetic resins, such as poly(meth)acrylate, polyurethane, polyvinylether, polyester, etc--a list of suitable matrix materials appearing e.g. in DE-OS 3500 508, to which reference is made. It can be advantageous if the reservoir matrix is contact adhesive, because this can obviate the need for providing a separate contact adhesive fixing device in the system. The use if such a contact adhesive matrix is inter alia dependent on the compatibility of the matrix material with the active substance. Contact adhesive matrix materials are known.
Preferred non-contact adhesive matrix materials are polymers comprising poly(meth)acrylate, polyvinylpyrrolidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulosephthalate, polyvinylalcohol or copolymers thereof with vinyllaurate or maleic acid, vinylacetate or copolymers thereof with vinyllaurate or maleic acid; polyvinylether, butyl rubber and polycaprolactam.
For example the chambers can also be provided between a back-side reservoir matrix layer and a skin-side reservoir matrix layer.
The backing layer can be constituted by per se known active substance-impermeable materials, such as metal foils, plastic films or laminates thereof, as are well known to the expert.